U.S. patent number 7,084,150 [Application Number 10/692,662] was granted by the patent office on 2006-08-01 for analogs and prodrugs of buprenorphine.
This patent grant is currently assigned to Euro-Celtique S.A.. Invention is credited to F. Peter Boer, Robert Kupper.
United States Patent |
7,084,150 |
Boer , et al. |
August 1, 2006 |
Analogs and prodrugs of buprenorphine
Abstract
Disclosed are prodrugs and analogs of buprenorphine.
Inventors: |
Boer; F. Peter (Boyton Beach,
FL), Kupper; Robert (East Greenwich, RI) |
Assignee: |
Euro-Celtique S.A. (Luxembourg,
LU)
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Family
ID: |
32230225 |
Appl.
No.: |
10/692,662 |
Filed: |
October 24, 2003 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20040192714 A1 |
Sep 30, 2004 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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60421347 |
Oct 25, 2002 |
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Current U.S.
Class: |
514/279;
546/39 |
Current CPC
Class: |
C07D
489/12 (20130101); A61P 29/00 (20180101) |
Current International
Class: |
C07D
419/02 (20060101); A61K 31/438 (20060101) |
Field of
Search: |
;546/39,41 ;514/279 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
Other References
Imoto et al., Biol. Pharm. Bull., vol. 19 (2), pp. 263-267, 1996.
cited by examiner .
Stinchcomb et al, Pharmaceutical Research, vol. 12(10), pp.
1526-1529, 1995. cited by examiner.
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Primary Examiner: Davis; Zinna N.
Attorney, Agent or Firm: Davidson, Davidson and Kappel,
LLC
Parent Case Text
This application claims priority from U.S. Provisional Application
Ser. No. 60/421,347, filed on Oct. 25, 2002 the disclosure of which
is hereby incorporated by reference in its entirety.
Claims
We claim:
1. A compound of Formula I: ##STR00004## wherein R.sub.1 is a
moiety selected from the group consisting of alkylcarbonyl,
alkenylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl,
aryloxycarbonyl and heteroaryloxycarbonyl moieties; wherein the
alkyl portion of the alkylcarbonyl moiety is selected from the
group consisting of unsubstituted and substituted, straight-chain
and branched-chain alkyls having from 8 to 20 carbon atoms; or
wherein the alkyl portion of the alkyl carbonyl moiety is a cyclic
alkyl having from 3 to 20 carbon atoms; wherein the alkenyl portion
of the alkenylcarbonyl moiety is selected from the group consisting
of unsubstituted and substituted, straight-chain and branched-chain
and cyclic alkenyl moieties having from 2 to 20 carbon atoms;
wherein the aryl portion of the arylcarbonyl moiety is selected
from the group consisting of unsubstituted and substituted phenyl,
and phenylalkyl; wherein the alkyl portion of the phenylalkyl
contains from 1 to 3 carbon atoms; wherein the phenyl portion of
the phenylalkyl is unsubstituted or substituted; wherein the
heteroaryl portion of the heteroarylcarbonyl moiety is an aromatic
5- or 6-membered heterocyclic ring containing one or two
heteroatoms selected from the group consisting of nitrogen, oxygen,
and sulfur; or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1, wherein said straight-chain
alkyl is selected from the group consisting of octyl, dodecyl, and
palmityl; and said straight-chain alkyl is optionally substituted
with 1 or 2 substituents independently selected from the group
consisting of halo, hydroxy, alkoxy(alkoxy)x,
hydroxyalkoxy(alkoxy)x, amino, monoalkylamino, dialkylamino, nitro,
carboxyl, alkoxycarbonyl, and cyano, wherein x is an integer from 0
to 3 and the alkoxy contains from 1 to 5 carbon atoms.
3. The compound according to claim 1, wherein said cyclic alkyl is
selected from the group consisting of cyclopropyl, cyclobutyl,
cyclopentyl and cyclohexyl; and said cyclic alkyl is optionally
substituted with 1 or 2 substituents independently selected from
the group consisting of halo, hydroxy, alkoxy(alkoxy)x,
hydroxyalkoxy(alkoxy)x, amino, monoalkylamino, dialkylamino, nitro,
carboxyl, alkoxycarbonyl, and cyano, wherein x is an integer from 0
to 3 and the alkoxy portion of the alkoxycarbonyl contains from 1
to 5 carbon atoms.
4. The compound according to claim 1, wherein said alkenyl is
selected from the group consisting of vinyl, 1-propenyl, i-butenyl,
pentenyl, hexenyl, n-decenyl and c-pentenyl; and said alkenyl is
optionally substituted with 1 or 2 substituents independently
selected from the group consisting of halo, hydroxy,
alkoxy(alkoxy)x, hydroxyalkoxy(alkoxy)x, amino, monoalkylamino,
dialkylamino, nitro, carboxyl, alkoxycarbonyl, and cyano, wherein x
is an integer from 0 to 3 and the alkoxy portion of the
alkoxycarbonyl contains from 1 to 5 carbon atoms.
5. The compound according to claim 1, wherein said phenylalkyl is
selected from the group consisting of benzyl, phenylethyl and
phenylpropyl; and the phenyl portion of the phenylalkyl is
optionally substituted with 1 to 3 substituents independently
selected from the group consisting of alkyl, hydroxy, alkoxy, halo,
amino, monoalkylamino, dialkylamino, nitro, carboxyl,
alkoxycarbonyl and cyano.
6. The compound according to claim 1, wherein said heteroaryl is
selected from the group consisting of pyridinyl, thienyl and
imidazolyl.
7. The compound according to claim 1, wherein R.sub.1 is selected
from group consisting of methoxyacetyl; ethoxyacetyl; benzoyl;
nicotinoyl; methoxycarbonyl; ethoxycarbonyl; propoxycarbonyl;
butoxycarbonyl; hexyloxycarbonyl; octyloxycarbonyl; and
imidazolylcarbonyl.
8. A compound of Formula II: ##STR00005## wherein n is an integer
from 0 to 3 and each R is independently selected from the group
consisting of hydrogen, methyl and ethyl; or a pharmaceutically
acceptable salt thereof.
9. A compound of Formula III: ##STR00006## wherein n is an integer
from 0 to 3 and each R is independently selected from the group
consisting of hydrogen, methyl and ethyl; or a pharmaceutically
acceptable salt thereof.
10. A pharmaceutical composition comprising a compound according to
any of claims 1 9 and a pharmaceutically acceptable carrier.
11. The pharmaceutical composition according to claim 10, wherein
said composition is in a form suitable for topical application
selected from the group consisting of a transdermal patch, gauze,
compress, ointment, cream, lotion, paste, gel, spray, aerosol and
oil.
12. The pharmaceutical composition according to claim 11, wherein
said form suitable for topical application is a transdermal
patch.
13. The pharmaceutical composition of claim 10 in a form selected
from the group consisting of an oral, sublingual, implantable,
intranasal, inhalable and parenteral dosage form.
14. A method for preparing a pharmaceutical composition comprising
combining a pharmaceutically acceptable excipient with a compound
of any of claims 1 9.
15. A method for the treatment of pain in a patient in need thereof
comprising applying to the skin of the patient an effective amount
of a compound of any of claims 1 9.
16. A pharmaceutical composition comprising a compound of Formula
I: ##STR00007## wherein R.sub.1 is a moiety selected from the group
consisting of alkylcarbonyl, alkenylcarbonyl, arylcarbonyl,
heteroarylcarbonyl, alkoxycarbonyl, aryloxycarbonyl and
heteroaryloxycarbonyl moieties; wherein the alkyl portion of the
alkylcarbonyl moiety is selected from the group consisting of
unsubstituted and substituted, straight-chain and branched-chain
alkyls having from 8 20 carbon atoms; or wherein the alkyl portion
of the alkyl carbonyl moiety is a cyclic alkyl having from 3 to 20
carbon atoms; wherein the alkenyl portion of the alkenylcarbonyl
moiety is selected from the group consisting of unsubstituted and
substituted, straight-chain and branched-chain and cyclic alkenyl
moieties having from 2 to 20 carbon atoms; wherein the aryl portion
of the arylcarbonyl moiety is selected from the group consisting of
unsubstituted and substituted phenyl, and phenylalkyl; wherein the
alkyl portion of the phenylalkyl contains from 1 to 3 carbon atoms;
wherein the phenyl portion of the phenylalkyl is unsubstituted or
substituted; wherein the heteroaryl portion of the
heteroarylcarbonyl moiety is an aromatic 5-or 6-membered
heterocyclic ring containing one or two heteroatoms selected from
the group consisting of nitrogen, oxygen, and sulfur; or a
pharmaceutically acceptable salt thereof; and a pharmaceutically
acceptable carrier; wherein the composition is in a form selected
from the group consisting of an oral, sublingual, implantable,
intranasal, inhalable and parenteral dosage form.
Description
BACKGROUND OF THE INVENTION
Buprenorphine, a partially synthetic opiate, has been contemplated
for prolonged analgesia via transdermal formulations. Buprenorphine
transdermal delivery systems are of particular interest because
buprenorphine is a potent, partial agonist opioid analgesic with
desirable therapeutic properties. For example, buprenorphine is 50
to 100 times more potent than morphine, but has a much safer
therapeutic index than morphine (see Wallenstein S L, et al.,
Crossover Trials in Clinical Analgesic Assays: Studies of
Buprenorphine and Morphine, Pharmacotherapy, G(5): 225 235, 1986).
Further, the partial agonist properties of buprenorphine are useful
in the treatment of opioid addiction.
There are several types of transdermal formulations of
buprenorphine reported in the literature. See, for example, U.S.
Pat. No. 5,240,711 (Hille et al.), U.S. Pat. No. 5,225,199 (Hidaka
et al.), U.S. Pat. No. 5,069,909 (Sharma et al.), U.S. Pat. No.
4,806,341 (Chien et al.), and U.S. Pat. No. 5,026,556 (Drust et
al).
The transdermal delivery of buprenorphine presents challenges to
the pharmaceutical formulator as up to 70% or more buprenorphine is
left in the patch after use due to the fact that buprenorphine
exhibits poor skin penetration. This presents problems with
formulating the dosage form and ensuring that a non-variable dosage
is delivered as prescribed. Also, the large amount of residual
buprenorphine remaining in the patch after use can be subject to
abuse and diversion.
There exists a need in the art for a transdermal application of a
compound which has the benefits of buprenorphine while minimizing
the associated formulation, dosing and abuse problems discussed
above.
OBJECTS AND SUMMARY OF THE INVENTION
In certain embodiments, the present invention is directed to a
prodrug of buprenorphine represented by Formula I below:
##STR00001## wherein R.sub.1 is a moiety selected from the group
consisting of alkylcarbonyl, alkenylcarbonyl arylcarbonyl,
heteroarylcarbonyl, alkoxycarbonyl, aryloxycarbonyl and
heteroaryloxycarbonyl moieties wherein the alkyl moiety is selected
from the group consisting of unsubstituted or substituted,
straight-chain, branched-chain and cyclic alkyl moieties having 1
20 carbon atoms; wherein the alkenyl moiety is selected from the
group consisting of unsubstituted and substituted, straight-chain,
branched-chain and cyclic alkenyl moieties having 2 20 carbon
atoms; wherein the aryl moiety is selected from the group
consisting of unsubstituted and substituted phenyl, and phenalkyl
moieties wherein the alkyl moiety contains 1 3 carbon atoms and the
phenyl moiety is unsubstituted or substituted; and the heteroaryl
moiety is a substituted or unsubstituted aromatic 5-or 6-membered
heterocyclic ring containing one or two heteroatoms selected from
the group consisting of nitrogen, oxygen, and sulfur; and
pharmaceutically acceptable salts thereof.
Examples of suitable straight-chain alkyl moieties in Formula I
include methyl, ethyl, propyl, butyl, hexyl, heptyl, octyl, dodecyl
and palnityl moieties and the like.
Examples of suitable branched-chain alkyl moieties include
isopropyl, sec-butyl, t-butyl, 2-methylbutyl, 2-pentyl and 3-pentyl
moieties and the like.
Examples of suitable cyclic alkyl moieties include cyclopropyl,
cyclobutyl, cyclopentyl and cyclohexyl moieties and the like.
Examples of suitable "alkenyl" moieties include vinyl (ethenyl),
1-propenyl, i-butenyl, pentenyl, hexenyl, n-decenyl and c-pentenyl
and the like.
The moieties may be substituted, generally with 1 or 2
substituents, wherein the substituents are independently selected
from halo, hydroxy, alkoxy(alkoxy)x, hydroxyalkoxy(alkoxy)x, amino,
mono- and dialkylamino, nitro, carboxyl, alkoxycarbonyl, and cyano
moieties, wherein x is an integer from 0 to 3 and the alkoxy
moieties contain from 1 to 5 carbon atoms.
By the expression "phenalkyl moieties wherein the alkyl moiety
contains 1 3 carbon atoms" is meant benzyl, phenethyl and
phenylpropyl moieties wherein the phenyl moiety may be substituted.
When substituted, the phenyl moiety of the phenalkyl group may
contain 1 3 substituents independently selected from alkyl,
hydroxy, alkoxy, halo, amino, mono- and dialkylamino, nitro,
carboxyl, alkoxycarbonyl and cyano moieties.
Examples of suitable "heteroaryl" moieties are pyridinyl, thienyl
and imidazolyl.
The expression "halo" is meant in the conventional sense to include
F, Cl, Br, and I.
Among the compounds represented by the general Formula I,
particular examples of compounds are those in which R.sub.1 is
selected from group consisting of acetyl; propionyl; butyryl;
valeryl; hexanoyl; isobutyryl; methoxyacetyl; ethoxyacetyl;
benzoyl; nicotinoyl; methoxycarbonyl; ethoxycarbonyl;
propoxycarbonyl; butoxycarbonyl; hexyloxycarbonyl;
octyloxycarbonyl; and, imidazolylcarbonyl.
In certain embodiments, the present invention is directed to an
analog of buprenorphine represented by Formula II below:
##STR00002## wherein n is an integer from 0 to 3 and each R is
independently selected from the group consisting of hydrogen,
methyl and ethyl.
In certain embodiments, the present invention is directed to a
prodrug of buprenorphine, represented by Formula III below:
##STR00003## wherein n is an integer from 0 to 3 and each R is
independently selected from the group consisting of hydrogen,
methyl and ethyl.
In certain embodiments, the present invention is directed to
pharmaceutical compositions comprising prodrugs of buprenorphine
represented by Formula I or III and a pharmaceutically acceptable
excipient.
In certain embodiments, the present invention is directed to
analogs of buprenorphine represented by Formula II and a
pharmaceutically acceptable excipient.
It is a further object of the present invention to prepare a
pharmaceutical composition comprising combining a compound of
Formula I, II or III with a pharmaceutically acceptable
carrier.
It is a further object of the present invention to provide a method
for the treatment of pain in patients comprising applying to the
skin of the patient an effective amount of a compound of Formula I,
II or III.
It is a further object of certain embodiments of the invention to
provide compounds of Formula I, II or III, which exhibit increased
skin penetration compared to buprenorphine.
It is a further object of certain embodiments of the invention to
provide a transdermal patch comprising a compound of Formula I, II
or III, which has a reduced percentage of active agent remaining in
the used patch as compared to buprenorphine.
For purposes of the present invention, the term "buprenorphine"
shall include buprenorphine base, pharmaceutically acceptable salts
thereof, stereoisomers thereof, and mixtures thereof.
DETAILED DESCRIPTION
The buprenorphine prodrug of the present invention, i.e., compounds
of Formula I and III, preferably demonstrate a higher lipophilicity
and biphase solubility than the active parent drug and hence are
better able to penetrate the skin of a human or non-human animal
and are capable of reverting to the active buprenorphine during or
after penetration through the skin. These characteristics make the
prodrugs useful for transdermal delivery of buprenorphine.
The buprenorphine analogs of the of the present invention, i.e.
compounds of Formula II, preferably demonstrate better absorption
characteristics than buprenorphine in order to promote the active
agent being absorbed by the skin. The analogs can be prepared by
modifying buprenorphine with ethylene oxide, propylene oxide,
butylene oxide or a mixture thereof.
The compositions according to the present invention can be combined
with a drug delivery device such as a patche, gauze or compress.
The compositions are also suitable for topical or intranasal
application as an ointment, cream, lotion, paste, gel, spray,
aerosol and oil. Suitable carriers for such formulations include
petroleum jelly, lanolin, polyethylene glycols, alcohols, and
combinations thereof.
In certain embodiments of the present invention, the compounds of
the present invention are administered transdermally. Preferable
transdermal delivery systems include transdermal patches,
transdermal plasters, transdermal discs, iontophoretic transdermal
devices and the like.
Transdermal dosage forms used in accordance with the invention can
include a backing layer made of pharmaceutically acceptable
material which is impermeable to a compound of the present
invention. The backing layer preferably serves as a protective
cover for compound, and may also provide a support function.
Examples of materials suitable for making the backing layer are
films of high and low density polyethylene, polypropylene,
polyvinylchloride, polyurethane, polyesters such as poly(ethylene
phthalate), metal foils, metal foil laminates of such suitable
polymer films and textile fabrics. Preferably, the materials used
for the backing layer are laminates of such polymer films with a
metal foil such as aluminum foil. The backing layer can be any
appropriate thickness which will provide the desired protective and
support functions. A suitable thickness will be from about 10 to
about 200 microns. Desirable materials and thickness will be
apparent to the skilled artisan.
In certain preferred embodiments, the transderrnal dosage forms
used in accordance with the invention contain a polymer matrix
layer. Generally, the polymers used to form the biologically
acceptable polymer matrix are those capable of forming thin walls
or coatings through which pharmaceuticals can pass at a controlled
rate. A non-limiting list of exemplary materials for inclusion in
the polymer matrix includes polyethylene, polypropylene,
ethylene/propylene copolymers, ethylene/ethylacrylate copolymers,
ethylenevinyl acetate copolymers, silicones, rubber, rubber-like
synthetic homo-, co- or block polymers, polyacrylic esters and the
copolymers thereof, polyurethanes, polyisobutylene, chlorinated
polyethylene, polyvinylchloride, vinyl chloride-vinyl acetate
copolymer, polymethacrylate polymer (hydrogel), polyvinylidene
chloride, poly(ethylene terephthalate), ethylene-vinyl alcohol
copolymer, ethylene-vinyloxyethanol copolymer, silicones including
silicone copolymers such as polysiloxane-polymethacrylate
copolymers, cellulose polymers (e.g., ethyl cellulose, and
cellulose esters), polycarbonates, polytetrafluoroethylene and
mixtures thereof.
Preferred materials for inclusion in the polymer matrix layer are
silicone elastomers of the general polydimethylsiloxane structures,
(e.g., silicone polymers). Preferred silicone polymers cross-link
and are pharmaceutically acceptable. Other preferred materials for
inclusion in the polymer matrix layer include: silicone polymers
that are cross-linkable copolymers having dimethyl and/or
dimethylvinyl siloxane units which can be crosslinked using a
suitable peroxide catalyst. Also preferred are those polymers
consisting of block copolymers based on styrene and 1,3-dienes
(particularly linear styrene-isoprene-block copolymers of
styrene-butadiene-block copolymers), polyisobutylenes, polymers
based on acrylate and/or methacrylate.
The polymer matrix layer may optionally include a pharmaceutically
acceptable cross-linking agent. Suitable crosslinking agents
include, e.g., tetrapropoxysilane.
Preferred transdermal delivery systems used in accordance with the
methods of the present invention include an adhesive layer to affix
the dosage form to the skin of the patient for a desired period of
administration, e.g., about 1 to about 7 days. If the adhesive
layer of the dosage form fails to provide adhesion for the desired
period of time, it is possible to maintain contact between the
dosage form and the skin by, for instance, affixing the dosage form
to the skin of the patient with an adhesive tape, e.g, surgical
tape. It is not critical for purposes of the present invention
whether adhesion of the dosage form to the skin of the patient is
achieved solely by the adhesive layer of the dosage form or in
connection with a peripheral adhesive source, such as surgical
tape, provided that the dosage form is adhered to the patient's
skin for the requisite administration period.
The adhesive layer preferably includes using any adhesive known in
the art that is pharmaceutically compatible with the dosage form
and preferably hypoallergenic, such as polyacrylic adhesive
polymers, acrylate copolymers (e.g., polyacrylate) and
polyisobutylene adhesive polymers. In other preferred embodiments
of the invention, the adhesive is a pressure-sensitive contact
adhesive, which is preferably hypoallergenic.
The transdermal dosage forms which can be used in accordance with
the present invention may optionally include a permeation enhancing
agent. Permeation enhancing agents are compounds which promote
penetration and/or absorption of the compounds of the general
Formula I, buprenorphine analogs and buprenorphine prodrugs into
the blood stream of the patient. A non-limiting list of permeation
enhancing agents includes polyethylene glycols, surfactants, and
the like.
Alternatively, permeation of the compounds of the present invention
may be enhanced by occlusion of the dosage form after application
to the desired site on the patient with, e.g. an occlusive bandage.
Permeation may also be enhanced by removing hair from the
application site by, e.g. clipping, shaving or use of a depilatory
agent. Another permeation enhancer is heat. It is thought that heat
enhancement can be induced by, among other things, using a
radiating heat form, such as an infrared lamp, onto the application
site after application of the transdermal dosage form. Other means
of enhancing permeation of the compounds of the present invention
such as the use of iontophoretic means are also contemplated to be
within the scope of the present invention.
In certain embodiments, the transdermal dosage form which may be
used in accordance with the present invention includes a
non-permeable backing layer made, for example, of polyester; an
adhesive layer made, for example of a polyacrylate; and a matrix
containing the compound of the present invention and other
desirable pharmaceutical aids such as softeners, permeability
enhancers, viscosity agents and the like.
The active agent may be included in the device in a drug reservoir,
drug matrix or drug/adhesive layer.
Certain preferred transdermal delivery systems also include a
softening agent. Suitable softening agents include higher alcohols
such as dodecanol, undecanol, octanol, esters of carboxylic acids,
wherein the alcohol component may also be a polyethoxylated
alcohol, diesters of dicarboxylic acids, such as
di-n-butyladiapate, and triglycerides particularly medium-chain
triglycerides of the caprylic/capric acids and coconut oil. Further
examples of suitable softeners are multivalent alcohols, for
example, levulinic acid, glycerol and 1,2-propanediol which can
also be etherified by polyethylene glycols.
A solvent may also be included in the transdermal delivery systems
of the present invention. A non-limiting list of suitable solvents
include those with at least one acidic moiety. Particularly
suitable are monoesters of dicarboxylic acids such as
monomethylglutarate and monomethyladipate.
Other pharmaceutically acceptable compounds which may be included
in the reservoir or matrix include: solvents, for example alcohols
such as isopropanol; permeation enhancing agents such as those
described above; and viscosity agents, such as cellulose
derivatives, natural or synthetic gums, such as guar gum, and the
like.
In preferred embodiments, the transdermal dosage form includes a
removable protective layer. The removable protective layer is
removed prior to application, and consists of the materials used
for the production of the backing layer described above provided
that they are rendered removable, for example, by a silicone
treatment. Other removable protective layers, for example, are
polytetra-fluoroethylene, treated paper, allophane, polyvinyl
chloride, and the like. Generally, the removable protective layer
is in contact with the adhesive layer and provides a convenient
means of maintaining the integrity of the adhesive layer until the
desired time of application.
Certain preferred transdermal dosage forms for use in accordance
with the present invention are described in U.S. Pat. No. 5,240,711
(Hille, et. al.; assigned to LTS Lohmann Therapie-Systeme GmbH
& Co.). The transdermal delivery device described therein
includes a backing layer which is impermeable to the buprenorphine,
a pressure-sensitive adhesive reservoir layer and optionally, a
removable protective layer. Preferably, the reservoir layer
includes about 10 to about 95%-wt polymeric material, about 0.1 to
about 40%-wt softener, about 0.1 to about 30%-wt buprenorphine. A
solvent for the buprenorphine base or pharmaceutically acceptable
salt thereof may be included as about 0.1 to about 30%-wt.
In a preferred embodiment, the transdermal delivery system is
prepared in accordance with the disclosure of International Patent
Application No. WO 96/19975 (Hille, et. al.; assigned to LTS
Lohmann Therapie-Systeme GMBH). In this device, the transdermal
delivery device contains resorption-promoting auxiliary substances.
The resorption-promoting auxiliary substance forms an undercooled
mass. The delivery system contains 10% buprenorphine base, 10 15%
acid (such as levulinic acid), about 10% softener (such as
oleyoleate), 55 70% polyacrylate, and 0 10% polyvinylpyrollidone
(PVP).
In other embodiments, the transdermal delivery system may be a
plaster such as that described in U.S. Pat. No. 5,225,199 to Hidaka
et al. Such plasters include a film layer including a polyester
film of about 0.5 to about 4.9 .mu.m thickness, about 8 to about 85
g/mm strength, respectively in the two directions intersecting
substantially at right angles, about 30 to about 150% elongation,
in the two directions intersecting substantially at right angles
and an elongation ratio of A to B of about 1.0 to about 5.0,
wherein A and B represent data in two directions intersecting at
right angles, and A is greater than B and wherein said polyester
film includes about 0.01 to about 1.0% by weight, based on the
total weight of the polyester film, of solid fine particles in
which the average particle size is about 0.001 to about 3.0 .mu.m
and an adhesive layer which is composed of an adhesive containing
transdermally absorbable drugs; wherein the adhesive layer is
laminated on said film layer over the surface in about 2 to about
60 .mu.m thickness. The average particle size is substantially not
more than 1.5 times the thickness of the polyester film.
The transdermal delivery system used in the present invention may
alternatively be prepared in accordance with U.S. Pat. No.
5,069,909 (Sharma et al.). This patent describes a laminated
composite which includes an impermeable backing layer providing a
protective covering for the composite which may be made from an
elastomeric polymer such as polyurethane, polyether amide, or
copolyester and may be about 15 250 microns in thickness. The
composite further includes a reservoir lamina composed of the drug
in an amount of 1 12% by weight and a pressure-sensitive adhesive,
e.g., polyisobutylene, or a silicone adhesive such as silastic, or
an acrylate adhesive, and 2 35% permeation enhancer (comprising
propylene glycol monolaurate in combination with capric acid or
oleic acid).
The transdermal delivery system used in the present invention may
alternatively be prepared in accordance with U.S. Pat. No.
4,806,341 (Chien et al.). This patent describes a transdermal
system of a pharmaceutical polymer matrix dosage unit having a
backing layer which is substantially impervious to the drug, and a
polymer matrix disc layer which is adhered to the backing layer and
which has microdispersed therein effective dosage amounts of the
drug. The polymer matrix may be a silicon polymer or copolymer,
such as methyl silicone polymer or copolymer, or methylvinyl
silicone polymer or copolymer. The polymer matrix layer preferably
has dispersed therein a skin permeation enhancing agent such as
isopropyl myristate, azone, or a combination of ethyl caprylate and
capryl alcohol.
The transdermal delivery system used in the present invention may
alternatively be prepared in accordance with U.S. Pat. No.
5,026,556 (Drust et al.). Described therein are compositions of the
drug in a carrier of a polar solvent material selected from the
group consisting of C.sub.3 C.sub.4 diols, C.sub.3 C.sub.6 triols,
and mixtures thereof, and a polar lipid material selected from the
group consisting of fatty alcohol esters, fatty acid esters, and
mixtures thereof; wherein the polar solvent material and the lipid
material are present in a weight ratio of solvent material:lipid
material of from 60:40 to about 99:1.
The transdermal delivery system used in the present invention may
alternatively be prepared in accordance with U.S. Pat. No.
4,588,580 (Gale, et. al.). This system comprises a reservoir for
the drug having a skin proximal, material releasing surface area in
the range of about 5 100 cm.sup.2 and containing between 0.1 and
50% by weight of the drug. The reservoir contains an aqueous gel
comprising up to about 47 95% ethanol, 1 10% gelling agent, 0.1 10%
drug, and release rate controlling means disposed in the flow path
of the drug to the skin which limits the flux of the drug from the
system through the skin. The release rate controlling means is more
permeable to the drug than to the ethanol, and may be, for example,
low density polyethylene (LDPE), ethylene-vinyl acetate (EVA)
copolymers, heat sealable polyesters, and elastomeric polyester
block copolymers, such as HYTREL.RTM. from DuPont. This system is
said to be capable of providing an administration rate of about 10
300 .mu.g/hr.
It is contemplated that each of the transdermal delivery systems
described herein may be modified by incorporating a compound of the
present invention to effect transdermal delivery of the compound.
Such modifications are within the abilities of one skilled in the
art of formulating transdermal delivery systems.
The prodrugs or analogs of the present invention can also be
included in a pharmaceutical composition selected from the group
consisting of an oral, sublingual, implantable, intranasal,
inhalable and parenteral dosage forms. When the prodrugs or analogs
are present in oral dosage forms, the agent can be combined with
excipients, i.e., pharmaceutically acceptable organic or inorganic
carrier substances suitable for oral administration which are known
to the art. Suitable pharmaceutically acceptable carriers include
but are not limited to water, salt solutions, alcohols, gum arabic,
vegetable oils, benzyl alcohols, polyethylene glycols, gelate,
carbohydrates such as lactose, amylose or starch, magnesium
stearate talc, silicic acid, viscous paraffin, perfume oil, fatty
acid monoglycerides and diglycerides, pentaerythritol fatty acid
esters, hydroxymethylcellulose, polyvinylpyrrolidone, etc. The
pharmaceutical compositions can be sterilized and if desired mixed
with auxiliary agents, e.g., lubricants, preservatives,
stabilizers, wetting agents, emulsifiers, salts for influencing
osmotic pressure buffers, coloring, flavoring and/or aromatic
substances.
The oral pharmaceutical compositions of the present invention can
be in the form of tablets, dragees, liquids, drops, gelcaps,
troches, lozenges, aqueous or oily suspensions, multiparticulate
formulations including dispersable powders, granules, pellets,
matrix spheroids or coated inert beads, emulsions, hard or soft
capsules or syrups or elixirs, microparticles (e.g., microcapsules,
microspheres and the like), buccal tablets, etc.
The compositions intended for oral use may be prepared according to
any method known in the art and such compositions may contain one
or more agents selected from the group consisting of inert,
non-toxic pharmaceutically acceptable excipients which are suitable
for the manufacture of tablets. Such excipients include, for
example an inert diluent such as lactose; granulating and
disintegrating agents such as cornstarch; binding agents such as
starch; and lubricating agents such as magnesium stearate. The
tablets may be uncoated or they may be coated by known techniques
for elegance or to delay release of the active ingredients.
Formulations for oral use may also be presented as hard gelatin
capsules wherein the active ingredient is mixed with an inert
diluent.
Aqueous suspensions preferably contain the prodrugs or analogs
thereof in a mixture that has one or more excipients suitable as
suspending agents, for example, pharmaceutically acceptable
synthetic gums such as hydroxypropylmethylcellulose or natural
gums. Oily suspensions may be formulated by suspending the
above-identified combination of drugs in a vegetable oil or mineral
oil. The oily suspensions may contain a thickening agent such as
beeswax or cetyl alcohol. A syrup, elixir, or the like can be used,
wherein a sweetened vehicle is employed. Injectable suspensions may
also be prepared, in which case appropriate liquid carriers,
suspending agents and the like may be employed.
The pharmaceutical compositions comprising the prodrugs or analogs
of the present invention can be prepared as immediate or sustained
release formulations. For example, a sustained release carrier can
be included in the formulation to provide a release of the agent or
salt thereof over a 12 to 24 hour period.
In certain embodiments the oral dosage form includes a
sustained-release material which is incorporated into a matrix
along with the prodrugs or analogs to provide for the sustained
release of the agent. The sustained-release material may be
hydrophobic or hydrophilic as desired. The oral dosage form of the
present invention may be prepared as granules, spheroids, matrix
multiparticulates, etc. which comprise the prodrugs or analogs in a
sustained release matrix, which may be compressed into a tablet or
encapsulated. The oral dosage form of the present invention may
optionally include other pharmaceutically acceptable ingredients
(e.g., diluents, binders, colorants, lubricants, etc.).
In certain embodiments, the oral dosage form of the present
invention may be an osmotic dosage form having a push or
displacement composition as one of the layers of a bilayer core for
pushing the prodrugs or analogs from the dosage form, and a
semipermeable wall composition surrounding the core, wherein the
wall has at least one exit means or passageway for delivering the
naltrexone from the dosage form. Alternatively, the core of the
osmotic dosage form may comprise a single layer core including a
controlled release polymer and the prodrugs or analogs.
All of the references cited herein, including the foregoing, are
hereby incorporated by reference in their entireties for all
purposes.
The following examples illustrate various aspects of the present
invention. They are not to be construed to limit the claims in any
manner whatsoever.
EXAMPLE 1
Preparation of 3,6-dipropionyl buprenorphine
A mixture of buprenorphine and propionic anhydride is stirred at a
suitable temperature. Upon cooling to room temperature, water is
added. The solution is partitioned between ether and potassium
hydroxide solution. The ether phase is separated, washed with
water, dried over anhydrous sodium sulphate and evaporated in
vacuo. The residue obtained is crystallized from ethanol-water to
yield the title compound.
EXAMPLE 2
Preparation of 3-propionyl buprenorphine
Propionic anhydride is added while stirring to a mixture of sodium
bicarbonate and buprenorphine hydrochloride in water. After
complete addition the mixture is stirred and extracted with
chloroform. The combined extracts are dried over anhydrous sodium
sulphate and evaporated in vacuo to yield the title compound.
EXAMPLE 3
Preparation of 3,6-diisobutyryl buprenorphine
The compound is prepared as described in Example 1, using
isobutyric anhydride instead of propionic anhydride. The compound
is recrystallized from ether-petroleum ether.
EXAMPLE 4
3,6-dihexanoyl buprenorphine
The compound is prepared as described in Example 1, using hexanoic
anhydride instead of propionic anhydride.
EXAMPLE 5
Preparation of 3-hexanoyl buprenorphine
The compound is prepared as described in Example 2, using the
equivalent amount of hexanoic anhydride instead of propionic
anhydride.
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